RDoC and translational perspectives on the genetics of trauma-related psychiatric disorders.
ABSTRACT: Individuals with a history of child abuse are at high risk for depression, anxiety disorders, aggressive behavior, and substance use problems. The goal of this paper is to review studies of the genetics of these stress-related psychiatric disorders. An informative subset of studies that examined candidate gene by environment (GxE) predictors of these psychiatric problems in individuals maltreated as children is reviewed, together with extant genome wide association studies (GWAS). Emerging findings on epigenetic changes associated with adverse early experiences are also reviewed. Meta-analytic support and replicated findings are evident for several genetic risk factors; however, extant research suggests the effects are pleiotropic. Genetic factors are not associated with distinct psychiatric disorders, but rather diverse clinical phenotypes. Research also suggests adverse early life experiences are associated with changes in gene expression of multiple known candidate genes, genes involved in DNA transcription and translation, and genes necessary for brain circuitry development, with changes in gene expression reported in key brain structures implicated in the pathophysiology of psychiatric and substance use disorders. The finding of pleiotropy highlights the value of using the Research Domain Criteria (RDoC) framework in future studies of the genetics of stress-related psychiatric disorders, and not trying simply to link genes to multifaceted clinical syndromes, but to more limited phenotypes that map onto distinct neural circuits. Emerging work in the field of epigenetics also suggests that translational studies that integrate numerous unbiased genome-wide approaches will help to further unravel the genetics of stress-related psychiatric disorders.
Project description:Post-traumatic stress disorder (PTSD) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. Genetic, epigenetic, and environmental factors act together to determine both an individual's susceptibility to PTSD and its clinical phenotype. In this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the PTSD phenotype. We discuss the importance of the epigenetic regulation of these candidate genes. We review the general epigenetic mechanisms that are currently understood, with examples of each in the PTSD phenotype. Our focus then turns to studies that have examined PTSD in the context of comorbid psychiatric disorders or associated social and behavioral stressors. We examine the epigenetic variation in cases or models of PTSD with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. We reviewed the literature that has explored epigenetic regulation in PTSD in adverse childhood experiences and suicide phenotypes. Finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of PTSD. We discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.
Project description:Early life stress (ELS) is highly related to the development of psychiatric illnesses in adulthood, including substance use disorders. A recent body of literature suggests that long-lasting changes in the epigenome may be a mechanism by which experiences early in life can alter neurobiological and behavioral phenotypes in adulthood. In this study, we replicate our previous findings that ELS, in the form of prolonged maternal separation, increases adult methamphetamine self-administration (SA) in male rats as compared with handled controls. In addition, we show new evidence that both ELS and methamphetamine SA alter the expression of the epigenetic regulator methyl CpG-binding protein 2 (MeCP2) in key brain reward regions, particularly in the nucleus accumbens (NAc) core. In turn, viral-mediated knockdown of MeCP2 expression in the NAc core reduces methamphetamine SA, as well as saccharin intake. Furthermore, NAc core MeCP2 knockdown reduces methamphetamine, but not saccharin, SA on a progressive ratio schedule of reinforcement. These data suggest that NAc core MeCP2 may be recruited by both ELS and methamphetamine SA and promote the development of certain aspects of drug abuse-related behavior. Taken together, functional interactions between ELS, methamphetamine SA, and the expression of MeCP2 in the NAc may represent novel mechanisms that can ultimately be targeted for intervention in individuals with adverse early life experiences who are at risk for developing substance use disorders.
Project description:As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post-genome-wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.
Project description:Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions.We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression).Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing.Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.
Project description:The NIMH Research Domain Criteria (RDoC) initiative aims to describe key dimensional constructs underlying mental function across multiple units of analysis-from genes to observable behaviors-in order to better understand psychopathology. The acute threat ("fear") construct of the RDoC Negative Valence System has been studied extensively from a translational perspective, and is highly pertinent to numerous psychiatric conditions, including anxiety and trauma-related disorders. We examined genetic contributions to the construct of acute threat at two units of analysis within the RDoC framework: (1) neural circuits and (2) physiology. Specifically, we focused on genetic influences on activation patterns of frontolimbic neural circuitry and on startle, skin conductance, and heart rate responses. Research on the heritability of activation in threat-related frontolimbic neural circuitry is lacking, but physiological indicators of acute threat have been found to be moderately heritable (35-50%). Genetic studies of the neural circuitry and physiology of acute threat have almost exclusively relied on the candidate gene method and, as in the broader psychiatric genetics literature, most findings have failed to replicate. The most robust support has been demonstrated for associations between variation in the serotonin transporter (SLC6A4) and catechol-O-methyltransferase (COMT) genes with threat-related neural activation and physiological responses. However, unbiased genome-wide approaches using very large samples are needed for gene discovery, and these can be accomplished with collaborative consortium-based research efforts, such as those of the Psychiatric Genomics Consortium (PGC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium.
Project description:BACKGROUND:Despite that the epidemiological studies on the comorbidity of alcohol misuse and psychiatric disorders have been studied, less is known about the magnitude of these disorders among patients with alcoholic liver disease (ALD). Our aim was to determine the prevalence of psychiatric and substance use disorders among hospitalized ALD patients in the United States. METHODS:We utilized a single-level clinical classification software to identify patients with ALD and psychiatric/substance use disorders from the 2011 National Inpatient Sample data. The primary outcome was the prevalence of these disorders among hospitalized patients with ALD (n = 74,972) compared to those with chronic liver diseases not caused by alcohol (n = 350,140) and those without underlying liver diseases (n = 1,447,063). RESULTS:The prevalence of adjustment disorder, anxiety disorder, posttraumatic stress disorder, and depression was significantly higher among hospitalized patients with ALD when compared to those with chronic liver diseases not caused by alcohol (all with p-values <0.05). Younger age, female gender, and White race were the independent predictors of psychiatric/substance use disorders among hospitalized patients with ALD. CONCLUSIONS:Hospitalized patients with ALD have significantly high prevalence of concomitant psychiatric and substance abuse disorders when compared to those with chronic liver diseases not caused by alcohol and those without underlying liver diseases. Screening and appropriate intervention should be implemented as part of routine clinical care for these patients.
Project description:Unexpected death of a loved one is common and associated with subsequent elevations in symptoms of multiple forms of psychopathology. Determining whether this experience predicts novel onset of psychiatric disorders and whether these associations vary across the life course has important clinical implications. The authors examined associations of a loved one's unexpected death with first onset of common anxiety, mood, and substance use disorders in a population-based sample.The relation between unexpected death of a loved one and first onset of lifetime DSM-IV disorders was estimated by using a structured interview of adults in the U.S. general population (analytic sample size=27,534). Models controlled for prior occurrence of any disorder, other traumatic experiences, and demographic variables.Unexpected death of a loved one was the most common traumatic experience and most likely to be rated as the respondent's worst, regardless of other traumatic experiences. Increased incidence after unexpected death was observed at nearly every point across the life course for major depressive episode, panic disorder, and posttraumatic stress disorder. Increased incidence was clustered in later adult age groups for manic episode, phobias, alcohol use disorders, and generalized anxiety disorder.The bereavement period is associated with elevated risk for the onset of multiple psychiatric disorders, consistently across the life course and coincident with the experience of the loved one's death. Novel associations between unexpected death and onset of several disorders, including mania, confirm multiple case reports and results of small studies and suggest an important emerging area for clinical research and practice.
Project description:The purpose of this study was to assess the test-retest reliability of substance use disorder and psychiatric modules in the Alcohol Use Disorder and Associated Disabilities Interview Schedule, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Version (AUDADIS-5).Kappa and intraclass correlation coefficients were calculated for DSM-5 substance use and psychiatric disorder diagnoses and dimensional criteria scales using a test-retest design among 1006 respondents drawn from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III).Reliabilities of substance use disorder diagnoses and associated criteria scales were generally good to excellent, while reliabilities for mood, anxiety and trauma and stress-related disorders and associated scales were generally in the fair to good range.The observed reliability of the DSM-5 diagnoses and dimensional scales for the substance use and psychiatric disorders found in this study indicates that the AUDADIS-5 can be a useful tool in various research settings, particularly in studies of the general population, the target population for which it was designed.
Project description:Very few studies have evaluated the reasons for referral to consultation-liaison (CL) psychiatry teams.This study aimed to evaluate the psychiatric morbidity pattern, reasons for referral and diagnostic concordance between physicians/surgeons and the CL psychiatry team.Two hundred and nineteen psychiatric referrals made to the CL psychiatry team were assessed for reason for referral and diagnostic concordance in terms of reason of referral and psychiatric diagnosis made by the CL psychiatry team.In 57% of cases, a specific psychiatric diagnosis was mentioned by the physician/surgeon. The most common specific psychiatric diagnoses considered by the physician/surgeon included depression, substance abuse, and delirium. Most common psychiatric diagnosis made by the CL psychiatric services was delirium followed by depressive disorders. Diagnostic concordance between physician/surgeon and psychiatrist was low (κ < 0.3) for depressive disorders and delirium and better for the diagnosis of substance dependence (κ = 0.678) and suicidality (κ = 0.655).The present study suggests that delirium is the most common diagnosis in referrals made to CL psychiatry team, and there is poor concordance between the psychiatric diagnosis considered by the physician/surgeon and the psychiatrist for delirium and depression; however, the concordance rates for substance dependence and suicidal behavior are acceptable.
Project description:CONTEXT:Psychiatric disorders and substance use during pregnancy are associated with adverse outcomes for mothers and their offspring. Information about the epidemiology of these conditions in this population is lacking. OBJECTIVE:To examine sociodemographic correlates, rates of DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking among past-year pregnant and postpartum women in the United States. DESIGN:National survey. SETTING:Face-to-face interviews conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions. PARTICIPANTS:A total of 43 093 respondents were interviewed, of whom 14 549 were women 18 to 50 years old with known past-year pregnancy status. MAIN OUTCOME MEASURES:Prevalence of 12-month DSM-IV Axis I psychiatric disorders, substance use, and treatment seeking. RESULTS:Past-year pregnant and postpartum women had significantly lower rates of alcohol use disorders and any substance use, except illicit drug use, than nonpregnant women. In addition, currently pregnant women had a lower risk of having any mood disorder than nonpregnant women. The only exception was the significantly higher prevalence of major depressive disorder in postpartum than in nonpregnant women. Age, marital status, health status, stressful life events, and history of traumatic experiences were all significantly associated with higher risk of psychiatric disorders in pregnant and postpartum women. Lifetime and past-year treatment-seeking rates for any psychiatric disorder were significantly lower among past-year pregnant than nonpregnant women with psychiatric disorders. Most women with a current psychiatric disorder did not receive any mental health care in the 12 months prior to the survey regardless of pregnancy status. CONCLUSIONS:Pregnancy per se is not associated with increased risk of the most prevalent mental disorders, although the risk of major depressive disorder may be increased during the postpartum period. Groups of pregnant women with particularly high prevalence of psychiatric disorders were identified. Low rates of maternal mental health care underscore the need to improve recognition and delivery of treatment for mental disorders occurring during pregnancy and the postpartum period.